Center of Excellence in Inflammation, Infectious Disease and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, TN.
Department of Internal Medicine, Division of Infectious, Inflammatory and Immunologic Diseases, Quillen College of Medicine, ETSU, Johnson City, TN.
Hepatology. 2021 Nov;74(5):2380-2394. doi: 10.1002/hep.32008. Epub 2021 Aug 25.
Hepatitis C virus (HCV) leads to a high rate of chronic infection and T cell dysfunction. Although it is well known that chronic antigenic stimulation is a driving force for impaired T cell functions, the precise mechanisms underlying immune activation-induced T cell dysfunctions during HCV infection remain elusive.
Here, we demonstrated that circulating CD4 T cells from patients who are chronically HCV-infected exhibit an immune activation status, as evidenced by the overexpression of cell activation markers human leukocyte antigen-antigen D-related, glucose transporter 1, granzyme B, and the short-lived effector marker CD127 killer cell lectin-like receptor G1 . In contrast, the expression of stem cell-like transcription factor T cell factor 1 and telomeric repeat-binding factor 2 (TRF2) are significantly reduced in CD4 T cells from patients who are chronically HCV-infected compared with healthy participants (HP). Mechanistic studies revealed that CD4 T cells from participants with HCV exhibit phosphoinositide 3-kinase/Akt/mammalian target of rapamycin signaling hyperactivation on T cell receptor stimulation, promoting proinflammatory effector cell differentiation, telomeric DNA damage, and cellular apoptosis. Inhibition of Akt signaling during T cell activation preserved the precursor memory cell population and prevented inflammatory effector cell expansion, DNA damage, and apoptotic death. Moreover, knockdown of TRF2 reduced HP T cell stemness and triggered telomeric DNA damage and cellular apoptosis, whereas overexpression of TRF2 in CD4 T cells prevented telomeric DNA damage.
These results suggest that modulation of immune activation through inhibiting Akt signaling and protecting telomeres through enhancing TRF2 expression may open therapeutic strategies to fine tune the adaptive immune responses in the setting of persistent immune activation and inflammation during chronic HCV infection.
丙型肝炎病毒（HCV）可导致高比例的慢性感染和 T 细胞功能障碍。虽然众所周知，慢性抗原刺激是导致 T 细胞功能障碍的驱动力，但 HCV 感染期间免疫激活诱导的 T 细胞功能障碍的确切机制仍不清楚。
在这里，我们证明了慢性 HCV 感染患者的循环 CD4 T 细胞表现出免疫激活状态，这表现在细胞活化标志物人类白细胞抗原-抗原 D 相关物、葡萄糖转运蛋白 1、颗粒酶 B 和短命效应标志物 CD127 杀伤细胞凝集素样受体 G1 的过度表达上。相比之下，慢性 HCV 感染患者的 CD4 T 细胞中干细胞样转录因子 T 细胞因子 1 和端粒重复结合因子 2（TRF2）的表达明显低于健康参与者（HP）。机制研究表明，HCV 参与者的 CD4 T 细胞在 T 细胞受体刺激时表现出磷酸肌醇 3-激酶/蛋白激酶 B/哺乳动物雷帕霉素靶蛋白信号的过度激活，促进前炎性效应细胞分化、端粒 DNA 损伤和细胞凋亡。在 T 细胞激活过程中抑制 Akt 信号可保留前体记忆细胞群体并防止炎症效应细胞的扩增、DNA 损伤和凋亡性死亡。此外，TRF2 的敲低降低了 HP T 细胞的干性并引发了端粒 DNA 损伤和细胞凋亡，而 CD4 T 细胞中 TRF2 的过表达则防止了端粒 DNA 损伤。
这些结果表明，通过抑制 Akt 信号调节免疫激活，并通过增强 TRF2 表达保护端粒，可能为慢性 HCV 感染期间持续免疫激活和炎症背景下微调适应性免疫反应提供治疗策略。
